RNF6 promotes myeloma cell proliferation and survival by inducing glucocorticoid receptor polyubiquitination

Ren，Ying1; Xu，Xin1; Mao，Chen yu2; Han，Kun kun1; Xu，Yu jia1; Cao，Bi yin1; Zhang，Zu bin1; Sethi，Gautam3; Tang，Xiao wen4; Mao，Xin liang1,4,5

2020-03-01

10.1038/s41401-019-0309-6

ACTA PHARMACOLOGICA SINICA   Impact Factor & Quartile

1671-4083

1745-7254

RNF6, a RING-type ubiquitin ligase, has been identified as an oncogene in various cancers but its role in multiple myeloma (MM) remains elusive. In the present study we first showed that the expression levels of RNF6 in MM were significantly elevated compared with the bone marrow cells of healthy donors. Overexpression of RNF6 in LP1 and PRMI-8266 MM cell lines promoted cell proliferation, whereas knockdown of RNF6 led to apoptosis of MM cells. Furthermore, we revealed that RNF6, as a ubiquitin ligase, interacted with glucocorticoid receptor (GR) and induced its K63-linked polyubiquitination. Different from current knowledge, RNF6 increased GR stability at both endogenous and exogenous contexts. Such an action greatly promoted GR transcriptional activity, which was confirmed by luciferase assays and by the increased expression levels of prosurvival genes including Bcl-xL and Mcl-1, two typical downstream genes of the GR pathway. Consistent with these findings, ectopic expression of RNF6 in MM cells conferred resistance to dexamethasone, a typical anti-myeloma agent. In conclusion, we demonstrate that RNF6 promotes MM cell proliferation and survival by inducing atypical polyubiquitination to GR, and RNF6 could be a promising therapeutic target for the treatment of MM.

apoptosis dexamethasone glucocorticoid receptor multiple myeloma RNF6 ubiquitin-proteasome pathway

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English

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WOS:000514159600011

PHARMACOLOGY & TOXICOLOGY

2-s2.0-85074325000

Scopus

1.Department of Pharmacology,College of Pharmaceutical Sciences,Soochow University,Suzhou,215123,China
2.School of Medicine,South University of Science and Technology,Shenzhen,518055,China
3.Department of Pharmacology,Yong Loo Lin School of Medicine,National University of Singapore,Singapore,117600,Singapore
4.National Clinical Research Center for Hematologic Diseases,Jiangsu Institute of Hematology,The First Affiliated Hospital of Soochow University,Suzhou,215100,China
5.Protein Modification and Degradation Key Lab of Guangzhou and Guangdong,School of Basic Medical Sciences,Affiliated Cancer Hospital and Institute of Guangzhou Medical University,Guangzhou,511436,China

Ren，Ying,Xu，Xin,Mao，Chen yu,et al. RNF6 promotes myeloma cell proliferation and survival by inducing glucocorticoid receptor polyubiquitination[J]. ACTA PHARMACOLOGICA SINICA,2020,41(3):394-403.

Ren，Ying.,Xu，Xin.,Mao，Chen yu.,Han，Kun kun.,Xu，Yu jia.,...&Mao，Xin liang.(2020).RNF6 promotes myeloma cell proliferation and survival by inducing glucocorticoid receptor polyubiquitination.ACTA PHARMACOLOGICA SINICA,41(3),394-403.

Ren，Ying,et al."RNF6 promotes myeloma cell proliferation and survival by inducing glucocorticoid receptor polyubiquitination".ACTA PHARMACOLOGICA SINICA 41.3(2020):394-403.